Depression is a major cause of disability in the world, and developing novel therapeutic approaches for its treatment is of utmost importance. Recent studies have suggested that interventions that have beneficial effects on mood such as exercise and chronic antidepressant treatment increase hippocampal neurogenesis. In addition, hippocampal neurogenesis is required for some of the behavioral effects of chronic antidepressant treatment. Adult-born granule cells (GC) in the DG exhibit a heightened synaptic plasticity during a critical window of their development, an enhanced plasticity mediated by the NR2B subunit-containing NMDA receptors. Yet, it remains unknown what role this increased excitability in adult-born GCs plays in behavior. This proposal will test the hypothesis that blocking the ability for adult-born GCs to contribute to plasticity in the DG has detrimental effects on cognitive function and antidepressant efficacy in mice. Specifically, the experiments proposed will test the effect of deletion of the NR2B subunit specifically in adult-born GCs on DG physiology, contextual fear learning and behavioral response to antidepressants. PUBLIC HEALTH RELEVANCE: This proposal is the first attempt to assess the impact of strategies aimed at modulating plasticity in adult born neurons. A potential application of these findings would be that pharmacological interventions aimed at modulating hippocampal neurogenesis might be beneficial for the treatment of mood or cognitive disorders.